Santi Cazorla bagged a brace in the first Liga fixture of 2019 as Villarreal held Real Madrid to their first draw under Santiago Solari.
Madrid bounced back from an early Cazorla goal to lead 2-1 until the former Arsenal midfielder re-emerged with a late header to not only lift Villarreal out of the relegation zone but also leave Los Blancos fourth in the table.
Casemiro had been sidelined with an ankle injury, forcing him to miss Madrid's last four League games, but the midfielder replaced Marcos Llorente, who was nursing a muscle tear.
Elsewhere, Solari named a near-full strength XI, with the back four picking itself and Isco continuing on the substitutes' bench, although Mariano Diaz and Marco Asensio remained out.
Villarreal, meanwhile, were a point adrift of safety and drew 1-1 with Huesca in Luis Garcia's first match at the helm before Christmas.
The match was played on Thursday, given it was rescheduled due to Los Merengues' Club World Cup commitments, and Cazorla took just four minutes to delightfully curl a first-time shot past Thibaut Courtois.
However, Madrid responded with two quick-fire goals as Karim Benzema nodded in a cross, before Raphael Varane climbed highest from a free kick to glance a header past Sergio Asenjo.
The offside flag correctly chalked off Luka Modric's rebound from a spilled Toni Kroos strike, while the lively Samuel Chukwueze forced Thibaut Courtois into a save from point-blank range.
Madrid were dealt a blow when Gareth Bale was forced off with a knock at the break but nonetheless looked to have seen off the threat of a Yellow Submarine equaliser in the second half.
However, Cazorla ghosted into the visitors' box through the backdoor with just seven minutes remaining to head in a cross.
Villarreal 2-2 Real Madrid
Cazorla 4, 82 (V) Benzema 7, Varane 20 (RM)
Villarreal: Asenjo; Layun, Alvaro, Ruiz, Jaume; Caseres (Toko Ekambi 63), Fuego (Trigueros 82), Cazorla; Fornals; Chukwueze, Gerard (Bacca 68)
Real Madrid: Courtois; Carvajal, Varane, Ramos, Marcelo; Kroos (Vinicius 86), Casemiro, Modric (Valverde 64); Vazquez, Benzema, Bale (Isco 46)
Referee: Gonzalez Fuertes